PROJECT SUMMARY Articular cartilage is a highly specialized tissue that protects diarthrodial joints from forces associated with load bearing, and allows nearly frictionless motion between articular surfaces. Articular cartilage injury often leads to osteoarthritis (OA). OA currently affects more than 25 million people in the United States alone, making joint surface restoration a major priority in modern medicine. The regenerative capacity of adult articular cartilage has traditionally considered to be negligible, but several recent reports suggest that the regenerative potential of articular cartilage may be underestimated. Based on our preliminary data, we hypothesize that signaling through the Leukemia Inhibitory Factor Receptor-Glycoprotein 130/Janus Kinase/Signal Transducer and Activator of Transcription 3 (LIFR/gp130/JAK/STAT3) pathway is essential during devleopment, and can stimulate adult chondrocytes to assume a proliferative and migratory phenotype, similar to what occurs during fetal joint development, thereby promotimg the maintenance of articular cartilage. Moreover, we identified a novel small molecule termed Regulator of Cartilage Growth and Differentiation 423 (RCGD 423) that potently and selectively agonizes this pathway in a gp130-dependent manner. We therefore test whether manipulation of gp130-STAT3 signaling, both genetically or pharmacologically, can modulate the development and progression of OA. First, the role of LIFR and STAT3 signaling in establishment and maintenance of mouse cartilage during development will be defined. Next, we will test the consequences of gain and loss of STAT3 function in cartilage regeneration in a mouse injury model designed to mimic OA. The final set of experiments will evaluate the effects of RCGD 423 and test the hypothesis that this molecule acts by modulating gp130 signaling in mouse cartilage repair and degeneration. The experiments in this proposal are anticipated to define a novel function for LIFR-gp130/STAT3 signaling in cartilage establishment and repair, and to demonstrate that manipulation of this pathway can prevent degeneration in mouse models of osteoarthritis. If these experiments are successful, a critical new pathway regulating cartilage development, repair and degeneration will have been identified. In addition, a small molecule agonist of gp130 signaling that can slow the progression of articular cartilage degradation will be ready for pre-clinical testing and development.